Gender issues in cardiovascular diseases. Focus on energy metabolism

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Gender issues in cardiovascular diseases Focus on energy metabolism

Men and women differences in cardiovascular diseases

S&G differences in cardiovascular diseases are particularly well-reported because there is strong epidemiological evidence that men and women face different risks and have different outcomes. The annual number of adults having diagnosed with a heart attack or fatal coronary heart disease (CHD) increases with age, with an under-representation of women that vanishes with aging. In a middle-aged population, men develop heart failure more frequently and at a younger age than women. Thus women are less susceptible to undergo cardiovascular diseases during the pre-menopausal phase of life. Moreover, the Euro Heart Failure survey has established that among hospitalized patients suspected to have heart failure, the distribution of the severity of left ventricular systolic dysfunction shows that it is higher in men than in women with 61% of men but only 35% of women having moderate to severe systolic dysfunction. The manifestation of heart failure also differs between men and women. Independently of age, women develop more frequently heart failure with preserved ejection fraction (HFpEF), i.e. diastolic dysfunction, while men develop more heart failure with reduced ejection fraction (HFrEF). At present, there is no specific treatment for HFpEF.

Sexual dimorphism is also evident in cardiac remodeling with women exhibiting a more concentric form of myocardial hypertrophy and less fibrosis, than men.

Concerning ischemic heart disease, it occurs three to four times more often in men under 60 years of age and develops 7–10 years later in women, while after 75, women are the majority of patients. S&G is also a major determinant of the incidence, etiology, and clinical presentation of arrhythmias, as well as in access and response to arrhythmia therapies. The prevalence of the different forms of arrhythmias exhibits an important sexual dimorphism with, for example, an increased prevalence of Brugada syndrome in men (1F/9M) and long QT syndrome in women (3F:1M). Incidence and prevalence of atrial fibrillation (AF) are lower in women than men but atrial fibrillation is a much higher risk factor for cardiovascular disease and death in women while at present causality is not obvious. Female sex has now been included as an additional and independent risk factor in the calculation of the risk of stroke in AF (CHA2DS2-Vasc score). A recent analysis of patients undergoing AF ablation based on the United States Nationwide Readmissions Database, between 2010 and 2014 concluded that independent of age, co-morbidities, and hospital factors, women have higher rates of complications and readmissions following AF ablation than men.

Sex differences in experimental studies

Mechanistic pathways involved in sex differences in cardiovascular diseases have been excellently reviewed recently in-depth. Male and female hearts respond differently to experimentally-induced cardiac diseases. For example, rat hearts exhibit sex differences when subjected to aortic constriction; while males have early and pronounced cardiac dysfunction, females have delayed cardiac dysfunction but increased left ventricular hypertrophy. Cardiac transcriptomics also revealed sex differences, with increased protein synthesis capacity and deregulation of matrix remodeling in male hearts and less downregulation of metabolic genes in female hearts. A similar pattern was also observed in humans. Thus energy metabolism and extracellular matrix seem to be more preserved in females following aortic constriction.

With the development of genetically modified organisms, in particular mice, it had become evident that males and females often respond differently to lose or gain of function experiments. We will take a few examples of genetically modified animals with sex differences in the field of cardiac energy metabolism. One of the first examples is the mice knocked-out for the peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor implicated in the control of cellular lipid utilization. In these mice, inhibition of cellular fatty acid flux caused massive hepatic and cardiac lipid accumulation, hypoglycemia, and death in 100% of males, but only 25% of female PPARα−/− mice. This effect was reversed in males by treatment with estrogen, showing an interaction between lipid metabolism and sex hormones. Conversely, mice expressing a cardiac-specific dominant-negative form of the cyclic nucleotide regulatory element-binding protein (CREB) transcription factor, demonstrated significantly higher mortality in females compared to males. These females exhibited decreased cardiac content of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) and estrogen-related receptor-alpha (ERRα) content, two factors essential for mitochondrial biogenesis, as well as increased oxidative stress, decreased mitochondrial content, and exacerbated mitochondrial dysfunction, suggesting sex-related effects on cardiac mitochondrial function. However, in general, male mice appear more sensitive to genetic interventions than females, since female animals display lower mortality, less severe hypertrophy, and better-preserved function than males.

Role of mitochondria in sex differences

It becomes apparent that energy metabolism is central in cardiac cell pathophysiology. As cardiac muscle relies for more than 90% on oxidative phosphorylation for energy utilization, mitochondria play a central role in cardiac energy metabolism. Many examples have provided evidence that they are also involved in sex differences.

This could be at first surprising as mitochondria are exclusively maternally inherited. As such, natural selection on mitochondria operates only in females. Indeed, according to the endosymbiotic theory, mitochondria arise from archeobacteria that have colonized ancient eukaryotic cells some 1.45 billion years ago. Mitochondria thus possess their own circular DNA, coding for 13 proteins of some complexes of the respiratory chain, 2 ribosomal, and 22 transfer RNAs. However, during the course of mitochondrial genesis, many genes were transferred from the genome of the mitochondrial endosymbiont to the genome of the host. In mammals, the mitochondrial proteome contains more than 1000 proteins, not counting a wide array of splicing and post-translational variants that are encoded by the nuclear genome. Thus the possible sex- (and tissue-) specificity of mitochondria derives from the fact that the vast majority of proteins are encoded by the nucleus, translated, and imported in mitochondria by specific transport mechanisms. As such, mitochondria are under the influence of genetic, epigenetic, and hormonal factors known to influence sex specificity. Moreover, the mitochondrial biogenesis machinery is governed by nuclear co-activators and transcription factors that control replication and transcription of the mitochondrial genome and are responsive to steroid hormones. Thus mitochondria are under the control of the nucleus and are influenced by sex in a tissue-dependent manner.

Author: R. Ventura-Clapier, J. Piquereau, A. Garnier, M. Mericskay, C. Lemaire, B. Crozatier

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